Testing SIPA1L2 as a modifier of CMT1A using mouse models

Abstract

ABSTRACTCharcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validateSIPA1L2as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion inSIPA1L2and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction betweenSipa1l2deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement ofSipa1l2in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions betweenSipa1l2deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.